Summary: Tat protein of HIV-1, essential for virus replication, activates a variety of host factors, some of which play a critical role in the progression of HIV-1 infection. The focus of our research is to understand the mechanism by which Tat promotes HIV infection. Recently, we reported two functional domains Tat21-40 and Tat53-68 in the group M and Tat9-20 in HIV-1 group O subtype, respectively, of the Tat protein that are sufficient to promote HIV infection. These findings are potentially important to understand the progression of HIV pathogenesis and in the development of potential therapeutic applications. We prepared a synthetic construct comprising these functional Tat sequences (Tat-MPC), generated antibodies against it, and demonstrated that anti-HIV-Tat MPC antibodies efficiently inhibited Tat-induced viral activation in monocytes infected with laboratory as well as various clinical isolates, and substantially reduced Tat-mediated cytopathic effects in the infected cells. However, while Tat-MPC is highly immunogenic and is capable of producing inhibitory antibodies, it also induces virus replication in the infected cells and, therefore, may not be a suitable candidate for a HIV therapeutic vaccine. Currently, we are modifying the cysteine-rich and basic domains of Tat-MPC to block their functional activity, but maintain the immunogenecity. This construct will be tested for its ability to induce immune response and reduce progression of HIV disease in HIV-infected non-human primates.